7-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone represented by the following formula: is called aripiprazole, which is a compound useful as an agent for treating schizophrenia. For instance, a pharmaceutical composition containing aripiprazole is mentioned in EP-A-367141 as an agent for treating schizophrenia, and usefulness of aripiprazole as antipsychotic agents is mentioned in J. Med. Chem., Vol. 41, pp. 658–667 (1998).
Hitherto, aripiprazole has been prepared by a reaction of a carbostyril compound represented by the following general formula (2): (wherein X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group), with a piperazine compound represented by the following formula (3): in the presence of an inorganic or organic basic compound, in an organic solvent or in the absence of solvent. For example, in EP-A-367141, it is mentioned that the above-mentioned reaction can be carried out, if necessary, by adding an alkali metal iodide such as potassium iodide, sodium iodide or the like as the reaction accelerator; and in the working examples thereof (EP-A2-367141, page 5, lines 42–44) sodium iodide is used as the reaction accelerator. According to the process described in EP-A-367141, however, yield of the objective aripiprazole cannot exceed about 80%, even if the reaction accelerator is used.
According to EP-A-367141, the preparation of aripiprazole is carried out even in the absence of solvent. In the absence of solvent, however, the reaction can progress only slowly, and the reaction system is difficult to maintain in a uniform state by stirring, because the starting material compounds and the objective aripiprazole are both solid materials. Accordingly, the process described in EP-A-367141 is not suitable for industrial manufacture.
Further, the process described in EP-A-367141 is complicated in the procedure for obtaining the objective aripiprazole.
Since aripiprazole is used as an active ingredient of pharmaceutical drugs, it is desired to obtain the aripiprazole in a further higher purity. Further, for suppressing the manufacturing cost, it is desired to produce the aripiprazole in a further higher yield.